Woods Angela, Dickerson Kristina, Heath Richard, Hong Seung-Pyo, Momcilovic Milica, Johnstone Stephen R, Carlson Marian, Carling David
Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
Cell Metab. 2005 Jul;2(1):21-33. doi: 10.1016/j.cmet.2005.06.005.
AMP-activated protein kinase (AMPK) is the downstream component of a kinase cascade that plays a pivotal role in energy homeostasis. Activation of AMPK requires phosphorylation of threonine 172 (T172) within the T loop region of the catalytic alpha subunit. Recently, LKB1 was shown to activate AMPK. Here we show that AMPK is also activated by Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK). Overexpression of CaMKKbeta in mammalian cells increases AMPK activity, whereas pharmacological inhibition of CaMKK, or downregulation of CaMKKbeta using RNA interference, almost completely abolishes AMPK activation. CaMKKbeta isolated from rat brain or expressed in E. coli phosphorylates and activates AMPK in vitro. In yeast, CaMKKbeta expression rescues a mutant strain lacking the three kinases upstream of Snf1, the yeast homolog of AMPK. These results demonstrate that AMPK is regulated by at least two upstream kinases and suggest that AMPK may play a role in Ca(2+)-mediated signal transduction pathways.
AMP激活的蛋白激酶（AMPK）是激酶级联反应的下游组分，在能量稳态中起关键作用。AMPK的激活需要催化性α亚基的T环区域内的苏氨酸172（T172）磷酸化。最近，LKB1被证明可激活AMPK。在此我们表明，AMPK也可被钙/钙调蛋白依赖性蛋白激酶激酶（CaMKK）激活。CaMKKβ在哺乳动物细胞中的过表达会增加AMPK活性，而CaMKK的药理学抑制或使用RNA干扰下调CaMKKβ几乎可完全消除AMPK的激活。从大鼠脑部分离或在大肠杆菌中表达的CaMKKβ在体外可磷酸化并激活AMPK。在酵母中，CaMKKβ的表达可挽救缺乏Snf1上游三种激酶的突变菌株，Snf1是AMPK的酵母同源物。这些结果表明，AMPK受至少两种上游激酶的调节，并提示AMPK可能在钙介导的信号转导途径中发挥作用。
